Eur J Cardiothorac Surg 2007;31:406-412. doi:10.1016/j.ejcts.2006.11.053
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Analysis of the inflammatory response in endovascular treatment of aortic aneurysms
Edmo Atique Gabriel*,
Rafael Fagionato Locali,
Carla Cristina Romano,
Alberto José da Silva Duarte,
José Honório Palma,
Enio Buffolo
Federal University of Sao Paulo – Paulista School of Medicine (Division of Cardiovascular Surgery), Heart Hospital of Sao Paulo (HCOR), Tropical Illnesses Institute of University of Sao Paulo, Brazil
Received 4 August 2006;
received in revised form 8 November 2006;
accepted 15 November 2006.
* Corresponding author. Address: Napoleao de Barros Street, 715, 3rd floor, Vila Clementino, 04024-002 Sao Paulo-SP, Brazil. Tel.: +55 11 5576 4055; fax: +55 11 5571 2719. (Email: edag{at}uol.com.br).
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Abstract
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Objective: The objective of this study is to evaluate the inflammatory response caused by endovascular stents in the treatment of aortic aneurysms. Methods: Twenty-five patients underwent endovascular stent treatment from March through December 2005. The evolution of mediators (sedimentation velocity, C reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-alpha, intercellular adhesion molecule-1, L-selectin), inflammatory cells (leukocytes, lymphocytes, platelets), serum creatinine and body temperature within preoperative period and in the following postoperative periods — 1, 6, 24 and 48 h, 7 days, 1–3 months, was analyzed. In order to achieve statistic significance, Friedman test and Wilcoxon test were used, with index of significance of 5% (p
< 0.05). Results: Peak values of sedimentation velocity, C reactive protein and interleukin-6 were observed at 7 days (p
< 0.0001), 48 h (p
< 0.0001) and 24 h (p
< 0.0001), respectively. Tumor necrosis factor-alpha and interleukin-8 did not show statistically significant variability during the entire follow-up. In terms of intercellular adhesion molecule-1 and L-selectin, their expressive values were found in late phase of follow-up, although without statistical significance. Elevation of leukocytes count occurred in premature phase of follow-up (p
< 0.0001), while lymphocyte and platelet count occurred in a late phase of follow-up (p
< 0.0001). Serum levels of creatinine did not show significant variability during follow-up. The period between 24 and 48 h corresponded to major frequency for fever (p
< 0.0001). Conclusion: Individual mediators analysis and inflammatory cells demonstrated variability of their values during postoperative follow-up. This could help in the analysis of the inflammatory response evolution caused by endovascular stent treatment for aortic aneurysms in premature and late phases after implantation of the vascular prosthesis.
Key Words: Aortic aneurysm • Vascular prosthesis • Inflammatory mediators
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1. Introduction
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The introduction of percutaneous coronary interventions with stent implantation has substantially shifted the treatment of coronary artery disease. Evidence of chronic inflammatory reaction and endothelial dysfunction after stent implantation has been emerging and might be interfering with patient outcome. Endovascular repair of aortic aneurysm is an emergent therapeutic alternative consisting of insertion of an endoprosthesis via transvascular access (femoral, iliac, aortic). The main purpose is aneurysm exclusion from the systemic circulation. Insertion of a stent causes inflammatory repercussion in the aortic endothelium. This becomes apparent by macroscopic, microscopic and laboratory clinical studies [1–5].
Post-implantation syndrome is evidenced by the expression of organic effects originated from complex interactions between the vascular endothelium and the aortic endoprosthesis. There is no clear definition about this concept from the point of clinical and physiopathological view; the criteria postulated include leukocytosis, fever and/or coagulation disturbances. Some aspects can be listed as promoters of this syndrome: extensive endothelial activation after implantation of endoprosthesis, activation by contact between blood components and the endoprosthesis surface and ischemia–reperfusion lesion due to periods more delayed of femoral arteries clamping [6]. The objective of this study was to investigate the inflammatory response created by endovascular treatment of aortic aneurysms.
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2. Methods
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2.1 Patients’ characteristics
Between March and December 2005, 30 patients participated in this study, with ages between 43 and 80 years (mean 64.2 years), without distinction of ethnic and gender, all of them with the diagnosis of aortic aneurysm. These patients came from the Heart Hospital of Sao Paulo (HCOR) and the Division of Cardiovascular Surgery at the Federal University of Sao Paulo — Paulista School of Medicine (UNIFESP-EPM). Inclusion criteria were: true aortic aneurysm without clinic and/or tomographic signals of rupture, not traumatic chronic aorta dissection, favorable tomographic characteristics (compatibility between the proximal and distal neck diameters of the aortic aneurysm and endoprostesis diameter, aortic morphology without significant tortuosities, absence of expressive aneurysm dilatation in the visceral vessel topography such as celiac trunk and renal arteries), postoperative follow-up feasible to be done through the periodic re-evaluation. Exclusion criteria were: clinical and/or laboratory suspect of infection of any site, acute aortic dissection, traumatic aortic lesions, ruptured aneurysms, mycotic aneurysms, patients with previous implantation of endoprostesis, chronic renal failure on dialysis, auto-immune illnesses, conjunctive tissue illnesses (Marfan, Ehlers-Danlos), aortitis, associated neoplasias, immunodeficiencies, use of anti-inflammatory drugs, chemotherapy treatment or immunossupressants, clinical and/or tomographic indication for open surgery and difficulties for regular postoperative follow-up.
The cases in which patients did no attend the hospital re-evaluations were considered as lost of follow-up, those who contracted infectious illnesses from any etiology during the follow-up or presented with intraoperative complications that made impossible the continuity of the study (surgical reconstruction of femoral artery, laparotomy for retroperitoneal access to the iliac arteries in case of narrow femoral arteries, patients with expressive hemodynamic instability and/or shock states). There were five patients lost for follow-up, resulting in 25 patients (Table 1
). None of the patients who were included in this study underwent open surgery to treat aortic aneurysm because the main focus of research was to try defining the features of inflammatory response curve of some markers in a long time follow-up after aorta endoprosthesis implantation. Therefore, there was no control group because the only comparison would be between the preoperative serum values of some markers and their postoperative ones during a long follow-up.
2.2 Delineation of the study
2.2.1 Preoperative period
This study was approved by the Committee of Ethic in Research of UNIFESP — EPM and HCOR, and all patients included signed a informed consent. Samples of approximately 15 ml of venous blood were obtained via puncture of peripheral veins with needles, 24 h prior to surgery.
Collected blood was distributed in four tubes in vacuum — two yellow tubes containing gel in its inner (volume of 3.5 ml each); one purple tube containing chelation of calcium in its inner (volume 3 ml each); one dry red tube (volume of 5 ml each). The tubes were transported at environmental temperature to the Laboratory of Clinic Analysis in the HCOR, in a time inferior to 1 h after the collection.
2.2.2 Intraoperative period
The endovascular procedures to aortic aneurysms treatment were performed at Hemodynamic Room of HCOR and UNIFESP — EPM. A multidisciplinary team — cardiovascular surgeon, a cardiologist and vascular surgeon — participated in the surgical procedure.
2.2.2.1 Operative technique
2.2.2.1.1 Thoracic aneurysm
The first stage of this operation consists of a dissection of a femoral artery and isolation of it between two vascular clamps and the puncture of contralateral femoral artery and insertion in this last one of a 6 French introducer. After infusion of 5000 units of heparin intravenously, the dissected artery is punctured and 6 French introducer is inserted. Via this introducer pig-tail catheter is inserted under fluoroscopic guidance and aortography is performed. Via the introducer inserted in the dissected artery, a thread extra-stiff (Amplatz of 260 cm Cook Inc. or similar) is inserted and used as trail to the movement of the endoprosthesis, during the procedure of its implant. The choice of endoprosthesis results from information about previous tomography and intraoperative aortography.
2.2.2.1.2 Abdominal aneurysm
The first stage of this operation consists of dissection of both femoral arteries and isolation of them between two vascular clamps. After infusion of 5000 units of heparin intravenously, both arteries are punctured and a 6 French introducer is inserted into each artery. Via one of the introducers (generally in the left femoral artery), a pig-tail catheter is used for aortography. Generally by the introducer of the right femoral artery, it is introduced a thread extra-stiff, which is used as trail for the endoprosthesis. Based on previous tomography and on intraoperative aortography, the endoprosthesis is chosen with the most favorable diameter and compatible with suitable delivery. Considering that the abdominal aortic aneurysm is usually associated with tortuosities and dilatation of the iliac-femoral territory, it is also necessary to use endoprosthesis in this topography. We use the right femoral access for insertion and implantation of the endoprosthesis (bifurcated) destined to the major body of aorta. Next, two other endoprostheses are introduced via both femoral accesses, aiming at implantation in bilateral iliac-femoral segment, properly connected with a main endoprosthesis.
2.2.2.1.3 Thoracic–abdominal aneurysm
Both femoral accesses are obtained by dissection and, after infusion of 5000 units of heparin intravenously, the procedure is carried out in the same way as described previously.
2.2.3 Postoperative period
The patients were followed during the three subsequent months after endovascular procedure and in following times — 1, 6, 24 and 48 h, 7 days and 1–3 months. In these periods, blood samples were obtained in identical ways as described in Section 2.2.1 and taken to the HCOR laboratory to quantify the inflammatory mediators, dosage of serum creatinine and determination of hemogram.
2.3 Laboratory analyses
The analyses of blood samples in the different periods of time was performed at the Laboratory of Clinical Analysis in HCOR and at the Laboratory of Medical Investigation (LMI-56) of Tropical Illnesses Institute of University of Sao Paulo. The equipment used to the determination of C reactive protein (CRP) and sedimentation velocity (SV) values was respectively IMMULITE 100 and MicroTestlec-DPC Medlab. In order to measure the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), L-selectin, intercellular adhesion molecule (ICAM-1), the ELISA assay was set with antibody of capture (Countig — R&D) and detection (Biotinilado — R&D).
2.4 Statistic analyses
2.4.1 Description of the sample
The serum levels of CRP, TNF-alpha, IL-6, IL-8, L-selectin, ICAM-1, SV, creatinine, total leukocytes, lymphocytes and platelets were considered as quantitative varieties of numeric scale (parametric). Body temperature was considered as nonparametric variety. The values calculated in each time of follow-up, to each variable, were arranged in tables with the average, standard deviation and confidence interval.
2.4.2 Inferential analyses
In order to do the inferential analyses of nine times studied between themselves, from the same variable, it was used the Friedman test. This test was complemented by the Wilcoxon test to cases in which there were significant statistical difference pointed by the Friedman test. It was considered the index of statistic significance of 0.05 or 5%.
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3. Results
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The SV values were normal in the preoperative period and from 6 h on after the procedure began the ascension of its levels, increasing to its peak value in 7 days. The descent of its levels begins between 7 and 30 days and continued to decline until 3 months after the procedure. The levels of CRP had significant increase from 6 h on, resulting in peak value with 48 h. Between 48 h and 7 days, it was observed decrease in serum levels, and about the second month postoperative, the values of CRP were practically undetectable (Fig. 1
).
Results in relation to the inflammatory response curve of IL-6 showed elevation of its levels that was considerably premature (before the first hour after the end of procedure), achieving peak value with 24 h and, from then on, began to decrease in a way that in the first month postoperative, the values obtained were very similar to previous values of the procedure. The inflammatory curve response of IL-8 was characterized by absence of linearity of serum levels, considering that preoperative values have ever been elevated and presented decline until 24 h, when it began to increase until 48 h, being followed by a new descent until 3 months (Fig. 2
).
The peak level of ICAM-1 and L-selectin was identified in the first month postoperative, and after this period of time, it began a descent of levels of both markers. In relation to the previous period to the first month after the procedure, it was registered a larger variability and oscillation in the L-selectin levels and the serum values of ICAM-1 kept more stable (Fig. 3
).
Serum values of TNF-alpha obtained in this research presented considerable variability during the postoperative follow-up, highlighting the existence of high levels prior to the procedure. The period between 24 and 48 h was marked by larger frequency of detection of fever in the patients analyzed (Fig. 4
).
The total leukocytes and segmented neutrophils presented the same standard of variability in the course of follow-up, with significant predominance in the interval between 6 and 48 h after the procedure. The lymphocyte response increased from 6 h postoperative, keeping crescent levels until the end of follow-up, demonstrating, therefore, a later and more durable character of this inflammatory cell (Fig. 5
).
The platelets count kept normal (150,000–450,000/mm3) until 6 h postoperative, when there was decrease numerically irrelevant until 48 h. The higher values of platelets were observed on the 7th day postoperative. There was no statistically significant variability in relation to the serum levels of creatinine (Fig. 6
).
In summary, it is important to emphasize the inflammation markers by demonstrating their inflammatory response curves (Fig. 7
).
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Fig. 7. (A–D) Inflammatory response curves. (A) SV. (B) CRP. (C) IL-6, IL-8. (D) ICAM-1, L-selectin, TNF-alpha.
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There was statistically significant variability between different aortic aneurysm sites, inflammatory markers and cells in the first 24 h (SV, ICAM-1, lymphocytes), after 7 days (L-selectin), and after 48 h (serum creatinine), postoperatively.
There was statistically significant variability between the different sizes of the aortic aneurysms and inflammatory markers in first 48 h (TNF-alpha), after 2 months (IL-6, L-selectin), and after 24 h up to 2 months (serum creatinine), postoperatively.
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4. Discussion
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The use of endoprosthesis in the treatment of aortic aneurysms has become more and more viable, due to the possibility of reduction of operative risk, time of hospital stay and cost. This study is aimed at exploration of the behavior of different inflammatory markers in the endovascular treatment of aortic aneurysms, during the preoperative period and afterwards for a longer postoperative period [3,4]. Because we did not consider as included patients underwent open surgery to treat aortic aneurysms, a comparison with those receiving endovascular stent treatment was not possible. The inflammatory infectious and neoplasics states, are conditions more frequent of accelerated SV while classically the cardiac failure, hypofibrinogenemia, hypoproteinemia and polycythemia vera reduce the SV. The SV is a sensitive, but not specific test [7–9].
CRP can cause thrombosis and stimulate atherosclerosis, through synthase inhibition of endothelial nitric oxide (eNOS) and prostacyclin (PGI2), increase of activation inhibitor of plasminogen (PAI-1) and stimulus of tissue factor in mononuclear cells. High levels of CRP were reported on the 7th day postoperative in patients underwent endovascular procedure for aortic aneurysm [10].
IL-8 is chemoattractant of neutrophils and lymphocytes, as well as direct mediator of activation and accumulation of leukocytes in inflammatory sites. IL-6 is a chemokine secreted by mononuclear phagocytes, endothelium cells and lymphocytes T. It promotes production of proteins of acute phase such as fibrinogen and CRP in the liver. Secretion of IL-6 occurs during the open surgery as well in the endovascular treatment, due to ischemia/reperfusion injury and after exposition of leukocytes to materials of prosthesis. Various studies have showed high concentration of IL-6 in supernadants of thrombotic contents of abdominal aortic aneurysms. Plasmatic levels of IL-6 after implantation of stent in the abdominal aorta or femoral arteries increased on the 1st day postoperative [11–13].
L-Selectin causes interaction between endothelium/leukocytes cells, but the expression of ICAM-1 makes easier the rolling, mediated by L-selectin, of lymphocytes and neutrophils. Some studies suggest that one of the functions of ICAM-1 is to stabilize the lymphocytes rolling. Studies in vivo showed that reduction of 50% in expression density of L-selectin results in a decrease of 70% in migration of peripheral lymphoid tissue [14–16].
TNF-alpha promotes leukocyte infiltration, hypotension, fever, hypomethabolism and release of IL-6 and IL-8. It has been demonstrated that antibodies anti-TNF-alpha block expression of adhesion molecules, reduce procoagulant response and reduce releasing of chemokines such as IL-6 and IL-8. Infusion of TNF-alpha does not change the product levels of complement activation [12,17–19].
Emigration of leukocytes from the systemic circulation is controlled by interaction coordinated by multiple signals and adhesion molecules, in particular selectins, chemoattractants and integrins. The chemoattractants are a group of molecules that induce chemotaxis of leukocytes according to gradients [15].
Reduction of platelets count after implantation of endoprosthesis in the aorta as well as adhesion of platelets to the material of endovascular prosthesis have been described in relation to expansible stents with balloon (stainless steel) as well autoexpansible stents (nitinol) [10,20–22].
Individuals submitted to endovascular treatment for aortic aneurysm have a higher risk of developing renal insufficiency as consequence of using contrast, microembolization and, occasionally, inattentive occlusion of renal arteries [23].
The incident of fever after implantation of endoprosthesis has been described and can have various potential etiologies, including bacteria translocation, which can be justified by transitory splanchnic ischemia, and release of IL-6 [24,25].
The inflammatory response caused by implantation of endoprosthesis consists of a systemic response based on inflammatory markers released and clinical signs. This response is primarily caused by endothelial dysfunction which reflects a synergic role between the material of the vascular prosthesis and the endovascular surgical technique. It is worth highlighting that there are different conformations of this response according to the patient, the influence of endovascular procedure features, such as material of graft, thrombotic process, degree of endothelial aggression, and amount of intravenous contrast. In most cases, the systemic inflammatory response is not severe and does not cause serious consequences. In addition, aggressive use of drugs is recommended in the acute phase when patients present with expressive clinical signs of inflammation. In spite of changes in inflammatory markers, follow-up did not reveal serious clinical outcomes after aneurysm repair.
Summarizing, it can be concluded that the individual analysis of mediators and inflammatory cells demonstrated variability of their values during the follow-up postoperative period. This could help in the analysis of the inflammatory response, in premature and late phases, after implantation of vascular prosthesis.
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Acknowledgments
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The authors are grateful to Dr Tomas A. Salerno for his valuable assistance in the English language review.
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D. Hayoz
Editorial comment: Time course of the inflammatory response after endovascular repair of aortic aneurysms
Eur. J. Cardiothorac. Surg.,
March 1, 2007;
31(3):
412 - 413.
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Abstract
1. Introduction
